Integrins are a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpIIb/IIIa, the fibrinogen receptor, and .alpha..sub.v .beta..sub.3, the vitronectin receptor. The fibrinogen receptor gpIIb/IIIa is expressed on the platelet surface and it mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, et al., Blood., 1988, 71, 831.
The vitronectin receptor .alpha..sub.v .beta..sub.3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. The .alpha..sub.v .beta..sub.3 receptor expressed on the membrane of osteoclast cells is believed to play a role in the bone resportion process and contribute to the development of osteoporosis. Ross, et al., J. Biol. Chem., 1987, 262, 7703; Fisher, et al., Endochrinology 1993, 132, 1411; Bertolini et al., J. Bone Min. Res., 6, Sup. 1, S146 252; EP 528 587 and 528 586. The .alpha..sub.v .beta..sub.3 receptor expressed on human aortic smooth muscle cells stimulates their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, a recent study has shown that a .alpha..sub.v .beta..sub.3 antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Brooks, et al., Cell, 1994, 79, 1157. Thus, agents that would block the vitronectin receptor would be useful in treating diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer.
Alig et al., EP 0 381 033, Hartman, et al., EP 0 540,334, Blackburn, et al., WO 93/08174, Bondinell, et al., WO 95/18619, Bondinell, et al., WO 94/14776, Blackburn, et al. WO 95/04057, Egbertson, et al, EP 0 478 328, Sugihara, et al. EP 529,858, Porter, et al., EP 0 542 363, and Fisher, et al., EP 0 635 492, and many others disclose certain compounds that are useful for selectively inhibiting the fibrinogen receptor. PCT/US95/08306, filed Jun. 29, 1995 (SmithKline Beecham Corp.) and PCT/US95/08146 filed Jun. 29, 19951995 (SmithKline Beecham Corp.) disclose vitronectin receptor selective antagonists. However, there are few reports of compounds which are potentvitronectin receptor antagonists. It has now been discovered that certain appropriately substituted amino pyridine compounds are potent inhibitors of the vitronectin receptor. In particular, it has been discovered that the amino pyridine moiety may be combined with a fibrinogen atagonist template to prepare compounds which are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.